AU1848899A

AU1848899A - Preparation for substitution therapy, containing at least one progestogen and at least one estrogen

Info

Publication number: AU1848899A
Application number: AU18488/99A
Authority: AU
Inventors: Philippe Robert Marie Wilhelmus Ghislain Koninckx
Original assignee: Saturnus AG
Current assignee: Saturnus AG
Priority date: 1993-09-09
Filing date: 1999-02-26
Publication date: 1999-04-29

Description

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a

AUSTRALIA

PATENTS ACT 1990 i Ir jL r: :ia =t si r:f

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COMPLETE

SPECIFICATION

FOR A STANDARD

PATENT

ORIGINAL

Name of Applicant SATURNUS

AG

Philippe Robert Marie Wilhelmus Ghislain KONiNCKX Actual Inventor: Address of Service: BALDWIN SHELSTON

WATERS

MARGARET

STREET

SYDNEY NSW 2000 Invention Title: "PREPARATION FOR SUBSTITUTION THERAPY,

CONTAINING

AT LEAST ONE PROGESTOGEN AND AT LEAST ONE

ESTROGEN"

Details of Original Application No. 76952/94 dated 8th September 1994 The following statement is a full description of this invention, including the best method of performing it known to us:i I

P

i t; I i PREPARATION FOR SUBSTITUTION THERAPY, CONTAINING AT LEAST ONE PROGESTOGEN AND AT LEAST ONE ESTROGEN.

The present invention relates to a preparation for substitution therapy and for oral contraception. More particularly the present invention on the one hand relates to relieving the effects which occur because the ovaries decrease or stop production of female hormones, for instance during the menopause. The substitution therapy is mainly intended to induce amenorrhoea with negligible blood loss.

During and after the menopause these effects comprise hot flushes and nocturnal sweating, atrophy of the vagina 10 which can result in sexual difficulties, bone S'..decalcification, increase in heart and blood vessel disorders i and psychic symptoms with a causal connection that is usually difficult to demonstrate.

Up to the present different types of substitution therapy have been applied comprising a hormone treatment with Ione or more oestrogens and one or more progestogens.

According to a first therapy, low doses of oestrogens and progestogens are administered, but such a treatment is ineffective in respect of the decalcification and heart and 20 blood vessel disorders.

!i In another therapy the natural cycle of oestrogen and progestogen is followed as closely as possible. This V\ treatment inevitably results in menstruation and has the advantage of a reduced risk of cancer of the uterus.

According to yet another therapy only oestrogens are administered in a dose which lies below the threshold for menstrual bleeding. This treatment has the drawback however of an increased risk of cancer of the uterus.

i According to a most recently known therapy oestrogens and progestogens are administered continuousl such that the endometrium does not proliferate. This therapy has the drawback however of an unacceptably high incidence of slight, irregular blood loss.

i -2- The present invention relates to preparations designed for substitution therapy or oral contraception with substantielly continuous application.

EP-A-559 240 discloses preparations for substitution therapy and oral contraception in which the estrogen dose is constant and the progestogen dose is periodically alternated.

However, the improvement in inhibiting endometrium bleeding is minor. Above that, since the use of higher progestogen doses provided better results than lower doses it appears illogical to use periodically varying estrogen doses.

The present invention is based on the finding that surprising when using periodically varying estrogen doses the occurrence of blood loss and intermediate 10 bleeding is substantially avoided. The estrogen dose is herein oscillated such that estrogen-dominant and progestogen-dominant periods occur alternatingly with a Ssufficiently short periodicity. This short periodicity in the estrogen dose is necessary to avoid blood loss.

Purely by administering a dose of progestogen substantially constant in time and an Si estrogen varying in time between at least two dose levels, it was possible to induce the .desired amenorrhoea while no blood loss occurred over a longer period.

According to a first aspect, the invention consists in a preparation for substitution Stherapy andor oral contraception comprising at least one progestogen and at least one Sestrogen having dose means in association therewith wherein the progestogen dose is constant, and the estrogen dose varies to oscillate betweenanestrogendominantperiod and a progestogen dominant period with periodicity of less than 10 days.

According to a second aspect, the invention consists in a method of substitution therapy and/or oral contraception comprising the step of administering to a subject in need 2aof hormone substitution therapy or oral contraception at least one progestogen and at least one estrogen wherein the progestogen dose is constant, and the estrogen dose varies to oscillate between an estrogen dominant period and a progestogen dominant period ith a periodicity of less than 10 days.

Unless the context clearly requires otherwise, throughout the description and the claims, the words 'comprise', 'comprising', and the like are to beconstrued ir-ar.

Sinclusive as opposed to an exclusive or.exhaustive sense; that is to say, in the sense of S. "including, but not limited to".

I,*

e on w -'w It is noted that the preparation is formulated such that a substantially constant blood concentration is obtained for progestogen, while the estrogen concentration in the blood varies between two blood concentrations. The periodicity must be sufficiently short and is generally less than 10 days. The periodicity is usually less than 7 days. The periodicity generally lies between 2-9 days, preferably between 2-6 days. It will, however, be apparent that the periodicity is dependent on the estrogens and progestogens used and the applied doses. Both the periodicity and concentrations of estrogen and S. progestogen are easy to determine by routine experimentation.

-According to an embodiment of the invention the preparation contains a constant to 0 progestogen dose, while the estrogen dose oscillates between two levels. This preparation is recommended because there is a greater certainty of avoiding blood loss over a longer period.

According to another embodiment the preparation contains oscillating doses of progestogen and estrogen, in varying ratios however such that blood less is avoided and amenorrhoea is induced.

:Use can be made in general of all known progestogens, such as progesterone 300-900 mglday norethisterone acetate 2-5 mg/day medroxyprogesterone acetate 1-5 mg/day d-norgestrel 30-150 ggr/day desogestrel 30-150 jgrlday norgestimate 30-150 figrlday cyproterone acetate 0.2-2 mg/day 3a gestodene 10-150 igiday 3-ketodesogestrel 10-150 1 Rglday drospirenon 0.2-3.0 mg/day I or combinations thereof. it is noted that the preparation can contain one or more and estrogens.

It will be apparent that the quantity of progeStogen and estrogen depends on the i person (constitution and age), 4 the progestogen(s) and estrogen(s), anti-progestogen and anti-estrogen for use and the form of administering: same.

The progestogen and estrogen can each be present in an oral, transdermal, parenteral or implantable application form for substitution therapy. The preparation can for instance comprise an application form which contains the progestogen and estrogen, and a second like application form which contains the progestogen and an increased dose of estrogen.

The progestogen and estrogen can of course be present in like but separate forms of application or in mutually differing forms of application. The progestogen can for instance be an implantable application form while the oestrogen is administered orally, transdermally or parenterally in a dose which takes account of the required time period according to 15 the invention.

The oral application form to be used comprises tablets, Scapsules, syrup, solutions. The transdermal forms of application comprise gels, plasters. Strips can for instance be used wherein tablets with progestogen and oestrogen in the desired ratio and periodicity are arranged in time sequence.

The parentaral application form comprises injection fluid and the like. The implantable application form comprises for *:example a known implantable sustained release preparation.

The preparations for oral contraceptive comprise 25 estrogens and progestogans in common form.

Preparations according to the invention were administered over a period of 3-12 months to 40 women in the menopause. By making use of the combination preparations according to the invention a constant amenorrhoea-could be obtained in the case of more than 90% of the women, wherein the clinical tolerance was perceived as optimal, wherein the woman did not discern any subjective difference between a fixed or changing oestrogen dose with a periodicity of about one week.

Using the preparations according to the invention as oral contraceptive intermediate bleeding will be substantially reduced.

Example 1 A preparation according to the invention comprised tablets of the type A which contained 10 gamma aethinyl-estradiol, 1 mg estradiol valerianate and 0.5 mg Snorethisterone, and tablets of the type B which contained 15 gamma instead of 10 gamma aethinyl-estradiol. By altematingly administering the tablets A and B over a time period of 7 days an amenorrhoea could be induced without blood loss fora very long period of I Example 2 tmne.

3 "A preparation according to the invention comprised tablets of the type A which i to contained 1 mg norethisterone or 0.5 mg cyproterone acetate and 2 mg estradiol valerianate. The preparation moreover contained tablets of the type B having 3 mg instead of 2 mg estradiol valerianate. By using the preparation with alternate administering (4-5 days) of the tablets A and B or B and A an amenorrhoea could be induced without blood loss for a longer period of time.

.IS. 15 Exampile 3 A preparation according to the invention comprised tablets of the type A which contained 15 gamma aethinyl-estradiol and 1 mg oestradiol valerianate and 1 mg norethisterone. The preparation moreover contained tablets of the type B having 1.5 mg instead of 1 mg norethisterone. By alternatingly administering the tablets A and B with a periodicity of 4-7 days an amenorrhoea could be induced without blood loss for a very long period of time.

Example 4 A preparation according to the invention for oral contraceptive with optimal cycle control comprises tablets of type A comprising 20 gg aethinyl-estradiol and 75 pg gestoden. The preparation contained tablets of type B comprising 30 gig instead of 20 9Ig aethinyl-estradiol. Tablets A and B are used in four alternating periods of six days 2A -6- Example A preparation according to the invention for oral contraceptive with optimal cycle control comprises tablets of type A comprising 15 gg aethinyl-estradiol and 75 pg instead of 15 jtg aethinyl-estradiol- Tablets A and B are used in six alternating periods of four days In example 4 and 5 only aethinyl-estradiol is used in order to use a estrogen dose which is as low as possible. However, higher estrogen doses may be used. Instead of using a constant progestogen dose fluctuating doses may be use fluctuating simultaneously and/or progressively in view of the varying estrogen dose.

Example 6 A preparation for oral contraceptive according to the invention comprises tablets of S. type A comprising 20pg aethinyl-estradiol and 75 lg gestoden, and tablets of type B S. comprises 30 ug aethinyl-estradiol and 75 tg gestoden and 50 pg onapristone. The tablets A and B are used in four alternating periods of each six days. After four periods i "15 the whole cycle is repeated without allowing a free period.

Example 7 SA preparation according to the invention for hormone substitution treatment comprises tablets of type A comprising 2 .ug estradiol valerianate and 50 pg gestoden.

The tablets of type B comprised 3 pg estradiol valerianate and 25-100 g onapristone. By alternatingly administering the tablets A and B over a time period of seven days Samenorrhoea could be induced without blood loss for a very long period of time.

It is obvious for a skilled person in the examples that administration of antiprogestogen or anti-estrogen can be alternated (alone or simultaneously) with estrogens and/or progestogens.

S-

s -6a For jnistance, the antiProgest -Ogen is added in a constant dose to thle abovementiofled combinations of estrogens and I

I.

7 progestagens in products for hormone replacement therapy and for contraception.

s: -i r i t

Claims

3- r THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1. A preparation for substitution therapy and/or oral contraception comprising at least one progestogen and at least one estrogen having dose means in association therevith wherein the progestogen dose is constant, and the estrogen dose varies to oscillate between an estrogen dominant period and a progestogen dominant period with a periodicity of less than 10 days. 2. A preparation according to Claim 1 wherein the dosage of estrogen is selected to avoid blood loss. 3. A preparation according to any one of the preceding claims wherein a period of 10 oscillation of the estrogen dose is less than 7 days.
4. A preparation according to Claim 1 or Claim 2 wherein a period of oscillation of the estrogen dose is between 2 and 9 days.
5. A preparation according to any one of the preceding claims wherein a period of oscillation of the estrogen dose is between 2 and 6 days. 15 6. A preparation according to any one of the preceding claims wherein the doses of progestogen and estrogen are selected to avoid blood loss.
7. A preparation according to any one of the preceding claims wherein-the progestogen is selected from one or more members of the group consisting of progesterone
300-900 mg/day 20 norethisterone acetate 2-5 mgiday medroxyprogesterone acetate 1-5 mg/day d-norgestrel 30-150 jgr/day desogestrel 30-150 pgr/day i: 1- r ii i!: 1L -9- norgestimate 30-150 tgr/day cyproterone acetate 0.2-2 mg/day gestodene 10-150 pg/day 3-Ketodesogestrel 10-150 ig/day and drospirenon 0.2-3.0 mg/day A preparation according to any one of the preceding claims-wherein the estrogen is selected from one or more members of the group consisting of aethinylestradiol 5-15 gamma/day .oestradiol valerianate 1-4 mg/day oestradiol 1-2 mg/day conjugated oestragen 0.3-1.25 mg/day and oestriol 1-4 mg/day 11. A preparation according to any one of the preceding claims wherein the progestogen S. or estrogen further contains anti-progestogen. 12. A preparation according to any one of the preceding claims wherein the progestogen or estrogen further contains anti-estrogen. 13. A preparation according to any one of the preceding claims whereinthe estrogen is formulated for oral administration. 14. A preparation according to any one of Claims 1 to 12 wherein the estrogen is s 20 formulated for transdermal administration. A preparation according to any one of Claims I to 12 wherein the estrogen is Sformulated for parenteral administration. ii r" 16. A preparation according to any one of Claims 1 to 12 wherein the estrogen is formulated for an implant. 17. A preparation according to any one of Claims 1 to 16 wherein the progestogen is formulated for oral administration. 18. A preparation according to any one of Claims 1 16 wherein the progestogen is formulated for transdermal administration. 19. A preparation according to any one of Claims 1 to 16 wherein the progestogen is .formulated for parenteral administration. S* 20. A preparation according to any one of Claims 1 to 16 wherein the progestogen is formulated for an implant. 21. A method of substitution therapy and/or oral contraception comprising the step of .administering to a subject in need of hormone substitution therapy or oral contraception at least one progestogen and at least one estrogen wherein the progestogen dose is constant, and the estrogen dose varies to oscillate between an estrogen dominant period and a progestogen dominant period with a periodicity of S less than 10 days. 22. A method according to Claim 21 wherein the dosage of estrogen is selected to avoid blood loss. 23. A method according to Claim 21 or Claim 22 wherein a period of oscillation of the estrogen dose is less than 7 days. 24. A method according to Claim 21 or Claim 22 wherein a period of oscillation of the estrogen dose in between 2 and 9 days. A method according to any one of Claims 21 to 24 wherein a period of oscillation of the estrogen dose is between 2 and 6 days. -11- 26. A method according to any one of Claims 21 to 25 wherein the doses of progestogen and estrogen are selected to avoid blood loss. 27. The use of at least one progestogen and at least one estrogen for the manufacture of a medicament for substitution therapy and/or oral contraception, wherein the progestogen dose is constant and the estrogen dose varies to oscillate between an estrogen dominant period and a progestogen dominant period with a periodicity of less than 10 days. 28. The use of Claim 27 wherein the dosage of estrogen is selected to avoid blood loss. 29. The use of Claim 27 or 28 wherein a period of oscillation of the estrogen dose is 10 less than 7 days. i 30. The use of Claim 27 or 28 wherein a period of oscillation of the estrogen dose is between 2 and 9 days. 31. The use of any one of Claims 27 to 30 wherein a period of oscillation of the estrogen dose is between 2 and 6 days. 15 32. The use of any one of Claims 27 to 31 wherein the doses of progestogen and I estrogen are selected to avoid blood loss. 33. A preparation for substitution therapy substantially as herein described with reference to any one of the examples, but not including comparative examples. 34. A method of hormone substitution therapy and/or oral contraception substantially as herein described with reference to any one of the examples, but not including comparative examples. A composition comprising a progestogen substantially as herein described with Sreference to any one of the examples. I -12- 36. A composition comprising an estrogen substantially as herein described with reference to any one of the examples. DATED this 26th Day of February 1999 SATURNUS AG Attorney: RUTH M. CLARKSON Fellow Institute of Patent Attorneys of Australia of BALDWIN SHELSTON WATERS 7 -i 5